Enaminones are a class of enamines, i.e., .alpha.,.beta.-unsaturated amines analogous to enols. Enamines are Schiff bases, and are highly unstable in aqueous solutions. As such, enamines are used as potential prodrugs (agents which yield an amine on hydrolysis) providing a lipophilic, but acid-labile, carrier group to the active pharmacophore.
Enaminones are formed between a primary amine and a .beta.-dicarbonyl compound, often referred to as vinylogous amides, in which the amino group is linked through a carbon-carbon double bond to a keto group. These compounds are well known; see, The Chemistry of Enamines, S. F. Dyke, Ed., Cambridge University Press, Cambridge, U.K. (1973); Enamines: Synthesis, Structure and Reactions, A. G. Cook, Ed., Marcel Dekker, New York (1969).
Enaminones are stabilized relative to enamines of monocarbonyl compounds probably due to intramolecular hydrogen bonding derived from .beta.-diketones, such as acetylacetone, and such derivatives have found usefulness as prodrugs of amines. The physicochemical properties, uses, and the hydrolysis of enamines under a variety of conditions are also well known: P. Y. Sollenberger, R. B. Martin, J. Am. Chem. Soc. (1970) Vol. 94, 4261-4270; J. K. Coward, T. C. Bruice, J. Am. Chem. Soc. (1969), Vol. 91, 5329-5339; K. Dixon, J. V. Greenhill, J. Chem. Soc., Perkin Trans. 2 (1974), Vol. 2, 164-168; E. J. Stamhuis, W. Mass, J. Org. Chem. (1965), Vol. 30, 2156-2160; J. Kavalek, E1-Bahei Said, V. Sterba, Collect. Czech. Chem. Commun. (1978) Vol. 43, 2732-2739; L. R. Fedor, Int. J. Pharm. (1984), Vol. 22, 197-205; J. D. Loosen, H. Bundgaard, Arch. Pharm. Chem. Sci., Ed. (1986), Vol. 14, 53-63; V. H. Naringrekar, V. J. Stella, J. Pharm. Sci. (1990), Vol. 79, 138-146.
Research related to enaminones has been generally limited to the stability of these compounds and their ability to yield the primary or secondary amine on hydrolysis. Naringrekar and Stella recently reported disappointing results in the use of enaminones as prodrugs. There it was reported that enaminones formed between amines and cyclic 1,3-dicarbonyl compounds were significantly more stable than acyclic analogs. Two articles did cite the potential use of enaminones for biological purposes (G. Romussi, B. Parodi, G. Bignardi, G. Menozzi, P. Schenone, Il Farmaco-Ed. Sc. (1986) Vol. 41, 539-547; Y. Kase, M. Saita, K. Takahama, K. Masaki, T. Miyata, Jap. J. Pharmacol. (1974) Vol. 24, S127-S128). In the former reference, enaminones were evaluated for hypoglycemic effectiveness. However, the authors reported no interesting results. In the latter reference, a Japanese abstract, the authors reported MK 1-203 (5,5-dimethyl-3-(o-chloro)phenylamino-2-(N-piperidinylmethyl)cyclohex-2-en e-1-one), and MK 1-907 (5,5-dimethyl-3-(m-methoxy)phenyl-2-N-methyl-N-phenethylaminomethylcyclohe x-2-ene-1-one), each of which were potent analgesics with morphine-like, as well as anticonvulsant and papaverine-like, actions. No further data was provided nor any subsequent information was cited from their laboratories. Significantly, none of the reports suggest the use of enaminones as central nervous system agents, which may be effective for a variety of disorders, notably epilepsy, parkinsonism, Huntington's chorea and Alzheimer's disease.